EP1654302B1 - Thermosensitive poly (organophosphazenes), preparation method thereof and injectable thermosensitive polyphosphazene hydrogels using the same - Google Patents

Thermosensitive poly (organophosphazenes), preparation method thereof and injectable thermosensitive polyphosphazene hydrogels using the same Download PDF

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Publication number
EP1654302B1
EP1654302B1 EP04748477.9A EP04748477A EP1654302B1 EP 1654302 B1 EP1654302 B1 EP 1654302B1 EP 04748477 A EP04748477 A EP 04748477A EP 1654302 B1 EP1654302 B1 EP 1654302B1
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nhch
cooc
formula
cooch
mmol
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German (de)
English (en)
French (fr)
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EP1654302A1 (en
EP1654302A4 (en
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Soo-Chang Song
Bae-Houn Lee
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Korea Advanced Institute of Science and Technology KAIST
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Korea Advanced Institute of Science and Technology KAIST
Korea Institute of Science and Technology KIST
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G79/00—Macromolecular compounds obtained by reactions forming a linkage containing atoms other than silicon, sulfur, nitrogen, oxygen, and carbon with or without the latter elements in the main chain of the macromolecule
    • C08G79/02—Macromolecular compounds obtained by reactions forming a linkage containing atoms other than silicon, sulfur, nitrogen, oxygen, and carbon with or without the latter elements in the main chain of the macromolecule a linkage containing phosphorus
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G79/00—Macromolecular compounds obtained by reactions forming a linkage containing atoms other than silicon, sulfur, nitrogen, oxygen, and carbon with or without the latter elements in the main chain of the macromolecule
    • C08G79/02—Macromolecular compounds obtained by reactions forming a linkage containing atoms other than silicon, sulfur, nitrogen, oxygen, and carbon with or without the latter elements in the main chain of the macromolecule a linkage containing phosphorus
    • C08G79/025—Polyphosphazenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

Definitions

  • the present invention relates to a biodegradable polyphosphazene polymer showing a sol-gel behavior by a temperature change in aqueous solution, a preparation method thereof, and injectable thermosensitive polyphosphazene hydrogels using the same.
  • a hydrogel refers to a three-dimensional network structure formed from a polymer existing in aqueous solution.
  • the hydrogel is formed by a chemical crosslink by a covalent bond or by a physical crosslink through a physical crosslink between molecules.
  • a network structure formed by the physical crosslink is different from that formed by the chemical crosslink in that the structure is formed not by a crosslinking points like in the covalent bond but by a physical junction zone.
  • a polymer shows a sensitivity against an external stimulus such as temperature, pH, electricity, and etc., and a polymer showing a drastic phase transition by a temperature change is called as a thermosensitive polymer.
  • the thermosensitive polymer shows a phase transition behavior according to a temperature change in aqueous solution, and the phase transition is reversibly performed from sol to gel and from gel to sol according to a temperature change.
  • a physical network structure is formed by a hydrophobic interaction, and the hydrophobic interaction is observed in aqueous solution of a polymer having a side chain such as an aliphatic chain, a fluorine chain, an aromatic chain, etc.
  • a hydrogel formed by the physical crosslink does not use a chemical crosslinking agent harmful to a body, thereby being spotlighted as a drug delivering material.
  • a polymer showing a sol-gel characteristic by a temperature change includes a poly (N-isopropyl acrylamide), polyethyleneoxide-polypropyleneoxide- polyethyleneoxide (PEO-PPO-PEO) and polyethyleneoxide-polylactic, glycolic acid- polyethyleneoxide (PEO-PLGA-PEO), and etc., and researches for using them as injectable drug delivering material are actively being underway ( Advanced Drug Delivery Reviews, 54, 37 (2002), Journal of Controlled Release, 80, 9 (2002)).
  • poly (N-isopropyl acrylamide) is disadvantageous in that it is cytotoxic and not dissolvable in vivo.
  • F127 of the PEO-PPO-PEO shows a sol-gel behavior by a temperature change in a concentration of not less than about 20% of weight, but when used for a long period, F127 not only increases the concentration of cholesterol in plasma and triglycerides but also is not dissolved in vivo.
  • PEO-PLGA-PEO(Regel ® ) is dissolved in a physiological condition and becomes a gel state at a temperature near a body temperature, thereby being researched as an agent for locally delivering an anti-cancer drug.
  • that polymer was reported to show a sol-gel characteristic only in a high concentration of more than about 16 weight % ( Journal of Controlled Release, 62, 109 (1999 )).
  • polyphosphazene polymers obtained by substituting polydichlorophosphazene with methoxypolyethyleneglycol and amino acid ester are dissolved in water under a predetermined temperature, but have a phase transition behavior in a temperature more than the certain temperature when a temperature is gradually increased and are gradually hydrolyzed in aqueous solution ( Macromolecules 32, 2188 (1999 ), Macromolecules 32, 7820 (1999 ), Macromolecules 35, 3876 (2002 ), Korean patent No. 259,367 , No. 315,630 and American patent No. 6,319,984 and etc.).
  • phase transition behavior of the polyphosphazene polymers disclosed in said theses or patents is mainly a sol-precipitation.
  • a gel intensity is weak in a physiological condition or a phenomenon of a gel contraction is generated, thereby having a limitation in being applied as a drug delivering material.
  • KR2000 0002785A a polymer is disclosed which is a polyphosphazene, similar to Lee et al, except one of the two side chain types is attached to the polymer backbone via an O atom (see abstract).
  • an object of the present invention is to provide a polyphosphazene polymer suitable for being used as a material of an injectable drug delivering system and having a biodegradable sol-gel behavior by a temperature change, and an excellent gel characteristic at a temperature near a body temperature, a preparation method thereof, and injectable thermosensitive biodegradable hydrogels using the same.
  • the present invention relates to a polyphosphazene polymer represented by Formula 1, a preparation method thereof, and injectable thermosensitive polyphosphazene hydrogels using the same.
  • R represents CH 2 CH(CH 3 ) 2 , CH(CH 3 )C 2 H 5 , or C 7 H 7
  • R' denotes CH 2 COOC 2 H 5 or CH(CH 3 )COOC 2 H 5
  • R" denotes OC 2 H 5 , NHCH 2 COOC 2 H 5 , NHCH 2 COOC 7 H 7 , NHCH(CH 2 CH(CH 3 ) 2 )COOC 2 H 5 or NHCH(CH(CH 3 )C 2 H 5 ) COOC 2 H 5
  • n denote
  • the present invention solved a problem that a polyphosphazene polymer of Macromolecules 32, 2188 (1999 ), Macromolecules 32, 7820 (1999 ), Macromolecules 35, 3876 (2002 ), Korean patent No. 259,367 , No. 315,630 and American patent No. 6,319,984 , having a phase transition do not have a sol-gel characteristic suitable for being used as a drug delivering material.
  • a gelation temperature and a gel viscosity of a polyphosphazene polymer greatly vary according to a kind of amino acid ester, molecular weight of aminomethoxypolyethyleneglycol, and respective contents of them and the gel characteristic of a polyphosphazene polymer can be controlled by using said characteristic, and thereby completed the present invention.
  • the polyphosphazene polymer of the present invention has as a substituent, a polyethyleneglycol which has a greater molecular weight than that substituted at the polyphosphagene polymers disclosed in said documents, and a ratio of a hydrophilic substituent and a hydrophobic substituent existing in the polyphosphazene polymer was controlled to have an excellent gel characteristic even at a temperature near a body temperature, thereby having a physical characteristic suitable for being used as an injectable drug delivering material.
  • the hydrophilic substituent is aminomethoxypolyethyleneglycol having a molecular weight of at least 550, preferably 550-2500
  • the hydrophobic substituent is amino acid ester selected from the group consisting of leucineethylester, isoleucineethylester, phenylalanineethylester, glycinethylester, glycylglycinbenzylester, glycylglycinethylester, glycylleucineethylester and glycylisoleucineethylester.
  • depsipeptide ester selected from the group consisting of ethyl-2-(O-glycyl)glycolate and ethyl-2-(O-glycyl)lactate is a substituent for controlling a decomposition rate.
  • a polydichlorophosphazene linear polymer having an average molecular weight of 10 3 - 10 5 of the following Formula 3 was obtained by a thermal polymerization of phosphazene trimer of the following Formula 2 as described in Macromolecules, 28, 7566 (1995) besides Y.S.Sohn , and it was used as a starting material.
  • a preparation method of the polyphosphazene polymer of Formula 1 according to the present invention comprises the steps of:
  • Reaction Scheme 1 shows a summarized preparation processes of the polyphosphazene polymer according to the present invention.
  • R, R', R", a, b, c, d, n and m are the same as defined in Formula 1.
  • the compound of the Formula 3 is reacted with 0.1-1.9 equivalents of amino acid ethylester based on said one equivalent of compound of the formula 3 and represented as a Formula 4 or a salt thereof in the presence of 4 equivalents of triethylamine.
  • the salt of amino acid ethylester represented as the Formula 4 is preferably hydrogen chloride salt.
  • a reaction solvent includes tetrahydrofuran(THF), dioxane, dimethylformamide(DMF), chloroform, or toluene, and the reaction is performed for about 12-72 hours in a temperature of -60 - 50 °C.
  • a product of the step (1) is reacted with 0-1.9 equivalents of depsipeptide ester of Formula 5 or a salt thereof, or with amino acid ester, dipeptide ester of Formula 6 or a salt thereof, in the presence of 0-4 equivalents of triethylamine.
  • the salt of the compound of Formula 5 or Formula 6 is preferably oxalate or hydrogen chloride salt.
  • a reaction solvent acetonitrile can be used as a non-limiting example of a reaction solvent.
  • a reaction temperature is preferably 0 - 45°C, and a reaction time is about 12 - 72 hours.
  • the aminomethoxypolyethyleneglycol of Formula 7 used as a reaction material in the step (3) is prepared by the following method.
  • methoxypolyethyleneglycol is reacted with one equivalent of 4-toluenesulfonyl chloride in the presence of two equivalents of triethylamine for 12 hours by using chloroform as a solvent.
  • two equivalents of sodium azide is added to the mixture and reacted for 12-24 hours at a temperature of 70 - 80 °C in dimethylformami or acetnytril as a solvent, thereby obtaining methoxypolyethyleneglycolazide.
  • methoxypolyethyleneglycolazide is converted into aminomethoxypolyethyleneglycol by using two equivalents of triphenylphosphine and ten equivalents of water.
  • a product of the step (2) is reacted with two equivalents of aminomethoxypolyethyleneglycol of Formula 6 based on the remaining chlorines in the presence of four equivalents of triethylamine, thereby substituting all of the chlorines remained in the product of the step (2) with aminomethoxyglycol.
  • a reaction solvent tetrahydrofuran, dioxane, chloroform or toluene are preferably used, but these are non-limiting examples only.
  • a reaction temperature is 40 - 50°C, and a reaction time is about 48-72 hours.
  • a product of each step can be used in the next step without purification, and a pure desired product can be recovere from a reaction mixture of the step (3) by the following method.
  • the reaction mixture is centrifuged or filtered to remove the precipitates (for example, triethylammonium chloride, triethylammonium salt of oxalic acid, etc.) from the reaction mixture and the filtrate is concentrated under a reduced pressure until a small quantity of solvent remains. Then, the concentrated liquid is dissolved in THF, and excess amount of hexane is added to induce precipitation of a product and then filtered, which are repeated 2 to 3 times, thereby removing un-reacted aminomethoxypolyethyleneglycol, amino acid ester and depsipeptide.
  • a solid obtained by said processes is dissolved in a small amount of methanol, sequentially dialyzed by methanol and distilled water, and dried in a low temperature to obtain a pure compound of Formula 1.
  • the present invention also relates to thermosensitive hydrogels for injectable drug delivering material containing a polyphosphazene polymer of Formula 1 and having a distinct sol-gel characteristic with a temperature change.
  • the said hydrogels are the polyphosphazene polymer of Formula 1 dissolved in buffering solution, acid solution, base solution, salt solution or water in a concentration of 2-30 weight %, preferably in a concentration of 7-15 weight %.
  • a viscosity of the polymer was measured by dissolving the polymer in an aqueous solution of PBS of pH 7.4 in a concentration of 10 weight %, putting the polymer in a chamber of a viscometer (Brookfield DV-III+ Rheometer) provided with an automatic temperature control bath (TC-501), and increasing the temperature in the rate of 0.04°C per a minute with a shear rate of 0.1 -1.7.
  • poly(aminomethoxyethyleneglycol) 14.24 g, 25.89 mmol
  • triethylamine 5.24 g, 51.78 mmol
  • the reaction solution was centrifuged or filtered to remove an excess amount of precipitates (Et 3 N ⁇ HCl), and the filtrate was concentrated under a reduced pressure until a small quantity of solvent remained. Then, the concentrated solution was dissolved in THF, and a precipitation of a product was induced by adding excessive hexane and filtered, which were repeated 2 to 3 times. Then, the solid obtained by said processes was dissolved in a small amount of methanol, sequentially dialyzed by methanol and distilled water for 5 days each, and then dried in a low temperature, thereby obtaining 6.7 g (58% yield) of a final product of [NP(AMPEG550) 0.78 (IleOEt) 1.18 (GlyLacOEt) 0.04 ].
  • Poly(dichlorophosphazene) (2.00 g, 17.26 mmol) was dissolved in THF and then put into a dry ice-aceton bath, then isoleucineethylester hydrogen chloride salt (4.05 g, 20.71 mmol) and triethylamine (8.38 g, 82.84 mmol) were sequentially added thereto and reacted for 48 hours at room temperature. Then, poly(aminomethoxyethyleneglycol) (15.19 g, 27.62 mmol) havig a molecular weight of 550 and triethylamine (5.59 g, 55.24 mmol) were added thereto and reacted for 48 hours at 50°C.
  • poly(dichlorophosphazene) (2.00 g, 17.26 mmol) and isoleucineethylester hydrogen chloride salt (4.73 g, 24.16 mmol) were reacted in the presence of triethylamine (9.78 g, 96.64 mmol), and then reacted with poly(aminomethoxyethyleneglycol) (15.53 g, 20.71 mmol) having a molecular weight of 750 in the presence.of triethylamine (4.19 g, 41.42 mmol), thereby obtaining 9.0 g (70% yield %) of a final product [NP(AMPEG750) 0.65 (IleOEt) 1.35 ].
  • poly(dichlorophosphazene) (2.00 g, 17.26 mmol) and isoleucineethylester hydrogen chloride salt (4.05 g, 20.71 mmol) were reacted in the presence of triethylamine (4.19 g, 41.42 mmol), and then reacted with poly(aminomethoxyethyleneglycol) (30.38 g, 27.62 mmol) of a molecular weight of 1100 in the presence of triethylamine (5.59 g, 55.24 mmol), thereby obtaining 8.3g (50% yield) of a final product, [NP(AMPEG1100) 0.84 (IleOEt) 1.16 ].
  • poly(dichlorophosphazene) (2.00 g, 17.26 mmol) was reacted with phenylalanineethylester hydrogen chloride salt (5.15 g, 22.44 mmol) in the presence of triethylamine (9.08 g, 89.76 mmol), and then reacted with poly(aminomethoxyethyleneglycol) (18.12 g, 24.16 mmol) of a molecular weight of 750 in the presence of triethylamine (4.89 g, 48.33 mmol) thereby obtaining 9.4 g (yield 65%) of a final product, [NP(AMPEG750) 0.73 (PheOEt) 1.27 ].
  • poly(dichlorophosphazene) (2.00 g, 17.26 mmol) was reacted with leucineethylester hydrogen chloride salt (4.56 g, 23.30 mmol) in the presence of triethylamine (9.43 g, 93.20 mmol), and then reacted with poly(aminomethoxyethyleneglycol)(12.34 g, 22.44 mmol) of a molecular weight of 550 in the presence of triethylamine (4.54 g, 44.88 mmol), thereby obtaining 8.2 g (yield 75%) of a final product, [NP(AMPEG550) 0.69 (LeuOEt) 1.31 ].
  • the polyphosphazene polymer according to the examples and comparative examples of the present invention and the polyphosphazene polymer as disclosed in Macromolecules 35, 3876 (2002 ) were respectively dissolved in pH 7.4 PBS solution in a concentration of 10 weight % each, and a sol-gel behavior with a temperature change was observed.
  • Figure 1 is a picture showing a sol-gel behavior of the polyphosphazene polymer according to the present invention with a temperature change. As shown in Figure 1 , the polymer is a solution state at a temperature lower than 30°C but it is changed into a gel state at a temperature near a body temperature (37°C).
  • Table 1 shows the results of the experiment of gel characteristic of the polyphosphazene polymer (polymer 1 and 2) disclosed in Macromolecules 35. 3876 (2002 ) and the polyphosphazene polymer prepared in Examples and comparative examples 1 to 4 of the present invention according to a temperature change.
  • “Starting gel temp.” denotes a temperature at the time when the viscosity of an aqueous solution of a polymer (10 weight % PBS solution, pH 7.4) starts to be remarkably increased
  • “maximum gel temp.” denotes a temperature that a viscosity of an aqueous solution of a polymer (10 weight % PBS solution, pH 7.4) reaches to a maximum point
  • “maximum gel intensity” denotes a viscosity that a viscosity of an aqueous solution of a polymer (10 weight % PBS solution, pH 7.4) reaches to a maximum point.
  • Figure 2 shows a viscosity change of the polyphosphazene polymer represented as the polymers 1 and 2 in the table 1 and the polyphosphazene polymer according to Examples and comparative examples 1 to 3 of the present invention, due to a temperature change.
  • the polyphosphazene polymer prepared in Examples 1 and 2 of the present invention not only maintains the transparent gel characteristic at a temperature near 37°C, but also has a gel intensity enough to be used as a drug delivering material.
  • FITC-dextran (FITC-dextran, Mw 71,600) was used as a model drug for in vitro release behavior experiments of the polyphosphazene polymer.
  • an experiment object polymer was dissolved in a concentration of 10 weight % PBS solution, pH 7.4 at 4°C.
  • the model drug was put in a concentration of 0.1 weight % and then stirred at a low temperature to obtain a uniform solution.
  • the polyphosphazene polymer having a thermosensitive hydrogel characteristic that a sol state maintained in a low temperature is changed into a gel state near a body temperature and suitable for being used as an injectable drug delivering material, the preparation method thereof, and the injectable thermosensitive hydrogels using the same were provided.
  • the polyphosphazene polymer according to the present invention not only has a thermosensitive characteristic and a biodegradable characteristic in aqueous water, but also has proper characteristics for being used as an injectable drug delivering material such as a gelation temperature, a gel intensity, a decomposition speed, a drug release behavior, and etc. Therefore, the polymer according to the present invention is useful as an injectable material for delivering drugs and can be applied to various industry fields relevant to a tissue engineering.

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EP04748477.9A 2003-07-25 2004-07-23 Thermosensitive poly (organophosphazenes), preparation method thereof and injectable thermosensitive polyphosphazene hydrogels using the same Not-in-force EP1654302B1 (en)

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KR10-2003-0051521A KR100517643B1 (ko) 2003-07-25 2003-07-25 온도 감응성 폴리포스파젠계 고분자, 이의 제조방법 및이를 이용한 주입형 온도 감응성 폴리포스파젠 하이드로젤
PCT/KR2004/001864 WO2005010079A1 (en) 2003-07-25 2004-07-23 Thermosensitive poly (organophosphazenes), preparation method thereof and injectable thermosensitive polyphosphazene hydrogels using the same

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US (1) US7259225B2 (ko)
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KR102286453B1 (ko) 2019-06-19 2021-08-09 한국과학기술연구원 베타-사이클로덱스트린을 통한 호스트-게스트 상호작용에 의해 온도감응성 폴리포스파젠에 결합된 생리활성 물질을 포함하는 하이드로젤 포접 복합체 및 이의 용도
KR102262329B1 (ko) * 2019-11-29 2021-06-10 한국과학기술연구원 가역적 솔-젤 전이 특성이 변화된 온도감응성 하이드로젤 조성물 및 이의 용도
CN115991938B (zh) * 2022-11-28 2024-03-15 深圳市罗湖区中医院 一种聚磷腈聚合物水凝胶及其制备方法与应用

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